The Objectives of the project are (a) to arrive at a genetically driven clinical definition of schizophrenia, and (b) to reduce heterogeneity in schizophrenia by distinguishing phenotypic subgroups on the basis of careful diagnosis and assessment of biological correlates in MZ and DZ twins. The Specific Aims directly relate to the objectives, firstly by deriving the clinical definition of schizophrenia that has the highest genetic validity in a consecutive series of schizophrenic twins, using the MZ:DZ ratio. Such a definition will be of value in other genetic investigations such as those using linkage markers in multiplex schizophrenic families. In addition, study of the nonschizophrenic MZ co-twins will allow us to infer clinical co"elates for schizophrenia with subclinical genetic penetrance. The second aim of the study is to investigate biological correlates of schizophrenia in the same series of MZ and DZ twins, relating these to diagnosis and twin concordance in order to identify homogenous subgroups with varying genetic and other aetiological influences. As more is understood about the genetic basis of schizophrenia, so the importance of defining variants at high genetic risk vs. those non-genetic variants who do not confer risk on their biological relatives increases. Study Design: the proposal is based on the twin method, using the Maudsley Twin Register, an unparalled clinical resource of over 2000 mentally ill probands consecutively ascertained over the last 40 years. Clinical data on twins is stored in the Genetics Section, updated as the Maudsley casenotes are updated, and probands and co-twins traced to their current address at regular intervals. Thus the clinical material already available for study is impressive. The most recently ascertained cohort of 120 pairs of schizophrenic twins will be interviewed using the CASH clinical interview, and assessed using a series of paradigms which have either been implicated in aetiology or proposed as biological markers for schizophrenia. These are family history of major psychiatric disorder, motor laterality, neurological abnormality (both "soft" signs and named CNS disorders) minor physical anomaly, complex continuous performance and smooth pursuit eye movements. Medical and obstetric histories will also be noted.